The glucagon-like peptide-1 receptor (GLP-1R) regulates insulin secretion, carbohydrate metabolism and appetite, and is an important target for treatment of type II diabetes and obesity. Multiple GLP-1R agonists have entered into clinical trials, such as semaglutide, progressing to approval. Others, including taspoglutide, failed through high incidence of side-effects or insufficient efficacy. GLP-1R agonists have a broad spectrum of signalling profiles. However, molecular understanding is limited by a lack of structural information on how different GLP-1R agonists engage with the GLP-1R. In this study, we determined cryo-electron microscopy (cryo-EM) structures of GLP-1R-Gs protein complexes bound with semaglutide and taspoglutide. These revealed similar peptide binding modes to that previously observed for GLP-1. However, 3D variability analysis of the cryo-EM micrographs revealed different motions within the bound peptides and the receptor relative to when GLP-1 is bound. This work provides novel insights into the molecular determinants of peptide engagement with the GLP-1R.

中文翻译：

---

Semaglutide和taspoglutide结合的GLP-1R-Gs复合物的结构和动力学

胰高血糖素样肽1受体（GLP-1R）调节胰岛素分泌，碳水化合物代谢和食欲，是治疗II型糖尿病和肥胖症的重要靶标。多种GLP-1R激动剂已进入临床试验，如semaglutide，目前已获批准。其他药物，包括他斯波鲁肽，由于副作用高发或疗效不足而失败。GLP-1R激动剂具有广泛的信号传导谱。但是，由于缺乏有关不同的GLP-1R激动剂如何与GLP-1R结合的结构信息，分子的理解受到了限制。在这项研究中，我们确定了与semaglutide和taspoglutide结合的GLP-1R-Gs蛋白复合物的冷冻电子显微镜（cryo-EM）结构。这些揭示了与先前对于GLP-1观察到的相似的肽结合模式。然而，冷冻EM显微照片的3D变异性分析表明，结合GLP-1时，结合的肽段和受体内的运动不同。这项工作为肽与GLP-1R结合的分子决定因素提供了新颖的见解。